Acromegaly, a disorder of chronic, growth hormone excess, is associated with significant morbidity and mortality. Prevention of the long-term complications of acromegaly depends on both an accurate biochemical assessment of disease status and an understanding of the goals of therapy. The studies planned for the final two years of my K08 (DK02561) continue to examine new approaches to the evaluation and treatment of acromegaly utilizing a large cohort of patients with acromegaly and will focus on integrating the molecular, biochemical and clinical aspects of my initial studies. Studies will continue a careful biochemical assessment of this cohort with modern, sensitive techniques in order to further define the new criteria for cure suggested by our work to date. Studies will focus on a longitudinal follow up of this cohort examining detailed biochemical parameters and determining if certain patients are at risk for disease recurrence. Studies will now include a new direction, the assessment of a clinical marker of GH status, body composition analysis, and a correlation of this analysis with the biochemical measures. I will continue to analyze tumor specimens from this larger cohort for the presence of activating mutations in the alpha subunit of Gs and will determine if these mutations define a clinical phenotype and/or biochemical response to medical therapy. The studies in this proposal are a first step toward achieving a multifaceted understanding of the optimal biochemical and clinical goals for disease control of acromegaly and toward integrating the information from molecular analysis of these tumors into our treatment approach. The R03will proved vital added support in the final two years of my K08. The R03 funds will enable me to continue to employ a clinical research assistant whose help with my studies will allow me to devote the needed effort to broadening my clinical research projects and to developing my skills in clinical and basic research methods as well as new projects for future funding. My current environment continues to be ideally suited for achieving my goals. My collaboration with Dr. Kalmon Post, providing me with access to large numbers of both patients and pituitary tumor specimens, continues to be effective. I continue to receive instruction in the molecular techniques from Drs. Sharon Wardlaw and Streamson Chua. My new collaboration with Dr. Steven Heymsfield on the body composition studies will add an important new aspect to my studies. My sponsor, Dr. Wardlaw, continues to be committed to providing me with the guidance I need to pursue my research plans and to facilitate my transition to independent investigator.